No 44 - 2017

DANMAP 2016

The annual DANMAP report (Danish Integrated Antimicrobial Resistance Monitoring and Research Programme) provides an overview of the consumption of antimicrobial agents used for animals and humans and the development of resistance in bacteria collected from these.

The report also describes the occurrence of resistance in samples collected from fresh meet products. The report for 2016 gives a detailed account of the most relevant findings and results from 2016 and trends observed in the past 10-year period. The DANMAP report is the result of the collaborative efforts of DTU Food, DTU Vet and Statens Serum Institut. The reports have been published annually since 1995 and are the most comprehensive source for monitoring of antibiotic resistance in Denmark. The report is available at www.danmap.org. In the following, we summarise the main points concerning consumption and development of resistance in relation to humans.

Consumption

Total consumption of antimicrobials for patients
In 2016, the total human consumption of antimicrobials for systemic treatment was 18.47 DID (Defined Daily Doses per 1,000 inhabitants), divided into 16.45 DID in primary healthcare and 2.02 DID in the hospital sector.

Thus, the consumption was comparable to the total consumption in the two preceding years; 18.50 DID in 2015 and 18.58 DID in 2014.

The consumption has followed a declining trend since 2011, when the highest total consumption ever was recorded (19.31 DID), and is now close to the consumption recorded in 2007 (18.37 DID).

In 2016, a total of 49,605 kg of active substance was used for human treatment.

Antimicrobial consumption in primary healthcare
In the context of DANMAP, the consumption in primary healthcare is defined as any antimicrobial dispensed to non-hospitalized patients.

Primary healthcare thus includes all redeemed prescriptions issued by a GP, privately practicing medical specialist or dentist, and by hospital doctors when discharging a patient. Overall, these four groups account for nearly 90% of the total consumption of antimicrobials in Denmark. The hospital doctors’ share of the prescriptions has followed an increasing trend; in 2016 their share was 13%.

In the course of the past five years, the consumption in primary healthcare has decreased by 5.1% when stated as DID (from 17.34 DID in 2011 to the previously mentioned 16.45 DKD in 2016) . When stated as the number of prescriptions redeemed, the decrease was 18%; and, finally, the decrease was 17% when stated as the number of treated patients. Thus, the consumption decreased from 638 dispensed prescriptions or 325 treated patients per 1,000 inhabitants in 2011 to 522 prescriptions or 270 treated patients in 2016. Decreases are more limited when stated as DID because of concurrent substantial changes in the choice of the individual types of antimicrobials used for treatment. Thus, in the treatment of urinary tract infections, the preferred antimicrobial changed from sulfamethizol to pivmecillinam.

Pivmecillinam weighs relatively more when stated as DID, which will therefore increase the total consumption although less patients are treated.

In 2016, the penicillins remained the largest group of antimicrobials in primary healthcare as they accounted for altogether 65% of the total consumption. Beta-lactamase-sensitive penicillins (phenoxymethylpenicillin) accounted for 25% of the consumption, broad-spectrum penicillins (pivmecillinam, in particular) for 22%, and combination penicillins (amoxicillin with clavulanic acid) and beta-lactamase-resistant penicillins (dicloxacillin, in particular) accounted for 9% each. Over the past ten years, the consumption ofphenoxymethylpenicillin has decreased, whereas the use of both broad-spectrum penicillins and combination penicillins has increased considerably. Ten years ago, phenoxymethylpenicillins thus comprised 55% of the total penicillin consumption, whereas they only comprised 39% in 2016.

In 2007, the combination penicillins had been authorised for slightly less than a year and their share of the consumption was therefore negligible, whereas they comprised 14% of the total penicillin consumption in 2016. For broad-spectrum penicillins, this marked shift reflects the changes mentioned in the treatment of urinary tract infections. Similarly, for the combination penicillins, the shift reflects a change in treatment of airway infections (including the treatment of acute bronchitis/COLD).

Children and elderly people account for the greatest antimicrobial consumption. Among children, a considerable decrease was observed in the consumption, primarily in the 0-4-year age group where the number of prescriptions redeemed per 1,000 children has decreased by 43% over the past 10 years and the number of treated patients has decreased by 33%. Overall, children and adolescents (from 0 to 19 years of age) on average redeemed 355 prescriptions and 218 patients were treated per 1,000 children.

Antimicrobial consumption in the hospital sector
The hospital consumption is typically stated as defined daily doses per 100 bed-days (DBD) or per 100 admissions (DAD). When stated as DBD, the antimicrobial consumption at somatic hospitals decreased for the second time in ten years; from 103,0 DBD in 2015 to 98.98 DBD in 2016 (104.3 DBD in 2014). In the course of 10 years, the total consumption of antimicrobials increased by 36% as the consumption was 74.33 DBD in 2007. This increase may, in part, be accounted for by shorter treatment courses.

The average number of bed days per treatment now is reduced compared with previously, and hospitals have simultaneously increased their activity. When stated as DAD, the antimicrobial consumption decreased from 313.50 DAD in 2015 to 310.53 DAD in 2016. In the ten-year period from 2007 to 2016, the consumption increased by 1.2% when stated as DAD. As for primary healthcare, the penicillin group constituted the greatest share, a total of 54%, including beta-lactamase-sensitive penicillins 10%, beta-lactamase-resistant penicillins 9%, extended-spectrum penicillins 17% and combination penicillins 18% of the total hospital consumption. Thus, for the second year running, combination penicillins comprised the largest of the penicillin groups at the hospitals.

Just like for primary healthcare, the considerable increase in the consumption of combination penicillins at the hospitals is remarkable; from 2007 to 2016, the consumption of this drug group rose from 2.95 DBD to 18.04 DBD. This substantial increase is due mainly to the fact that piperacillin/tazobactam has become an important part of empirical sepsis treatment at most hospitals.

Consumption of critically important antimicrobials
In 2016, fluoroquinolones comprised 3% of the consumption in primary healthcare, a level that has remained stable for many years. In hospitals, fluoroquinolones accounted for 8%, cephalosporins 10% and carbapenems 4% of the total consumption, which is a decrease compared with 2007, when their combined share was 32% of the consumption. The reduced consumption is mainly owed to a decreasing consumption of fluoroquinolones and cephalosporins in the past 4-5 years. The consumption of carbapenems has been increasing steadily over the past ten years, but decreased for the first time from 4.10 DBD in 2015 to 3.98 in 2016.

Resistance

Monitoring of gastrointestinal infections
As in previous years, resistance to ampicillin, sulfonamide and tetracycline accounts for a high share of the total number of Salmonella typhimurium infections (65-71%); for tetracyclines, resistance has risen steadily. Resistance to these three antimicrobials is related to the monophasic variant of S. typhimurium that constitutes 64% of the total number of S. typhimurium infections. The occurrence of ciprofloxacin- and colistin-resistant S. typhimurium from travel-related infections (18% and 5%, respectively) is higher than among S. typhimurium infections acquired in Denmark (1% for both antimicrobials). None of the resistance-determined salmonella isolates from animals, meat or humans were resistant to meropenem.

Among Campylobacter jejuni detected in patients with travel-related infections, the occurrence of resistance to ciprofloxacin (80%) and tetracycline (59%) was markedly higher than in isolates from patients whose infection was acquired in Denmark (33% and 17%, respectively).

In 2016, a pilot study was conducted on the monitoring of Clostridium difficile in clinical samples. The study demonstrated that numerous types of C. difficile without the binary toxin dominate the Danish infection reservoir, regionally as well as nationally, and that these types are associated with a 30-day mortality that corresponds to that of the binary toxin-positive isolates. In 2017, the monitoring of C. difficile has therefore been changed from focusing on the binary toxin-positive isolates to also include samples of the binary toxin-negative isolates. The new monitoring regime is expected to yield improved monitoring of both existing and new emerging types and their associated toxin and resistance profiles.

Monitoring of invasive infections
For invasive Escherichia coli isolates, the past 6 years have seen a general stagnating trend in the occurrence of resistance to third-generation cephalosporins, gentamicin, piperacillin/tazobactam which have remained stable at around 7%, 6.5% and 4.5%, respectively.

In the same period, ciprofloxacin has continuously followed a decreasing trend with 11% ciprofloxacin-resistant invasive E. coli isolates in 2016 compared with 14% in the 2009-2012 period. There is, however, considerable variation in the occurrence of ciprofloxacin resistance in E. coli reported from the 11 Danish departments of clinical microbiology, as the occurrence varied from 4.1% to 27% in 2016.

The occurrence of resistance in invasive Klebsiella pneumoniae isolates remained unchanged in 2016 compared with 2015. It would thus appear that the downward trend observed for the period from 2009 to 2015 has levelled out at around 7.5% third-generation cephalosporin resistance, 3% gentamicin resistance and 5.5% ciprofloxacin resistance.

The combined resistance to third-generation cephalosporin, gentamicin and ciprofloxacin has remained at 2% in invasive E. coli and 1-3% in invasive K. pneumonia in the 2014-2016 period. Resistance to meropenem still only occurs sporadically in invasive E. coli and K. pneumoniae (1 and 3 isolates, respectively, in 2016).

The DANMAP 2016 report includes for the first time reporting of the occurrence of resistance in invasive Acinetobacter spp. for the years from 2012 to 2016. The period shows a significant decrease in the reported occurrence of resistance to meropenem, gentamicin and ciprofloxacin from 10.3%, 10.4% and 12%, respectively, to 0%, 0% and 2.8% among an annual 58-83 reported isolates.

For invasive Enterococcus faecium, 2016 recorded a substantial increase in the share of reported vancomycin-resistant isolates (VRE) from a level in the 3.4-4.3% range in the years 2013-2015 to 7.5% in 2016. This is seen as a result of the general increase in VRE observed in the same period. Resistance to Linezolid was first reported to DANMAP in 2016. One linezolid-resistant e. faecium isolate was detected among 417 tested invasive e. faecium isolates.

In 2016, the occurrence of resistance to penicillin and erythromycin remained low among Streptococcus pneumoniae in isolates from blood and spinal fluids (6% with reduced susceptibility to penicillin and 5% with erythromycin resistance).

Monitoring of other resistance mechanisms
In 2016, a total of 1,981 cases of bacteraemia with Staphylococcus aureus were reported. This corresponds to an incidence of 34.7 cases per 100,000 inhabitants. The number of bacteraemias with methicillin-resistant S. aureus (MRSA) was 40 (2.1%) compared with 29 (1.5%) in 2015. The number of MRSA bacteraemias was at par with the level observed the previous years, which is still very low compared with the other European countries. 2016 observed a total of 3,550 new cases of MRSA (infections and carrier state); for comparison, 2,972 cases were observed in 2015, EPI-NEWS 23/16. Infection was detected in 38% of the new cases, but in substantially fewer in the group that had become infected with livestock MRSA CC398 (17%).

Increases in the occurrence were mainly recorded among community-acquired MRSA cases (1,280 in 2016; 1,057 in 2015) and imported (712 in 2016; 500 in 2015) MRSA cases, whereas livestock MRSA CC398 stagnated in the three previous years (1,249 in 2016; 1,173 in 2015 but 1,277 in 2014). The occurrence of hospital-acquired cases remained very low at only 43 recorded cases in 2016.

2016 again saw an increase in the number of patients at Danish hospitals who had VRE infections. In 2016, a total of 434 VRE were reported compared with 371 VRE cases in 2015. The increased occurrence of VRE was primarily associated with hospital outbreaks, and the occurrence was most prominent in the Capital Region of Denmark and in Region Zealand.

In 2016, a total of 115 carbapenemase-producing organisms (CPO) were isolated from 99 patients; 9 of the isolates were from blood cultures and 4 of these were Enterobacter cloacae. This is an increase from 2015, when 91 CPO were reported from 85 patients.

Previously, findings of CPO have been travel-associated, but in recent years the source of several of the CPO findings has remained unknown or been related to Danish outbreaks.

Ciprofloxacin resistance among Neisseria gonorrhoeae was 18% in 2016 compared with 29% in 2015 and 46% in 2014. The highest occurrence of resistance to date was recorded in 2009 at 75%.

Commentary

The total human antimicrobial consumption has increased markedly compared to the consumption that was recorded at the end of the 90s, but since 2011 the consumption has started declining. This trend is seen most clearly when studying the number of prescriptions redeemed where a decrease has been observed in the past decade, but the most pronounced decrease is seen as from 2011. Numerous local initiatives in primary healthcare and also at hospitals aim to reduce the consumption even further, and to ensure a more expedient use. In 2017, efforts were initiated to reduce the use of antimicrobials at hospitals through the National Learning and Quality Teams.

Furthermore, the Danish Ministry of Health has published a national action plan for the use of antimicrobials, which, based on the consumption in 2016, stipulates three objectives for the reduction of the consumption until 2020.

Since 2011, the hospital sector has witnessed a reduction in the consumption of fluoroquinolones and cephalosporins, which presumably is associated mainly with changed treatment regimes for patients who are admitted with sepsis. For carbapenems, 2016 saw the first ever decrease in consumption. However, supply difficulties for piperacillin/tazobactam in 2017 may have a negative impact on the future development in the consumption of the critically important antimicrobials. Specifically, it may be necessary to use carbapenems, cephalosporins and/or fluoroquinolones for acutely ill patients. Here, the efforts made to ensure a more rational use is pivotal. These efforts include, among others, adaptation of the antimicrobial treatment to more narrow-spectrum regimes when a microbiological result is produced.

The occurrence of resistance in E. coli and K. pneumoniae was substantially higher in 2016 than 20 years earlier, but for some antimicrobials, no further increase in the occurrence of resistance has been observed since around 2010/11; and for K. pneumoniae, a decrease in the occurrence of resistance was even observed for some antimicrobials.

Unfortunately, this does not apply to the multi-resistant bacteria, where the increase in CPO and VRE is very concerning. A working group under the Danish Health Authority is currently preparing a guideline on prevention of the spreading of CPO. It is important that the Danish Health Authority’s recommendations are implemented rapidly at Danish hospitals.

The occurrence of MRSA increased in 2016. This trend was seen most clearly in the number of imported and community-acquired cases.

The observed stagnation in livestock MRSA CC398 may possibly have been recorded because many risk-group persons (with contact to livestock) have already been registered. At some point, a saturation in this group will therefore be seen. The same saturation is not going to be seen in the group with no livestock contact.

Therefore, there is a need for continued and improved monitoring of the spreading of the multi-resistant K. pneumoniae, E. coli, CPO, VRE and MRSA and for comprehensive infectious hygiene initiatives aiming to curb the spreading of infection.

(U.W. Sönksen, S.S. Olsen, S. Skovgaard, K.G. Kuhn, A. Petersen, J. Larsen, A.R. Larsen, M. Torpdal, S.Persson, E.M.Nielsen, S. Hoffmann, T. Dalby, L. Roer, F. Hansen, H. Hasman, A.M. Hammerum, Infection Preparedness at Statens Serum Institut, M. Laursen, Data Delivery & Medicinal Product Statistics, the Danish Health Data Authority)

Link to previous issues of EPI-NEWS

1 November 2017